Today's pharmaceutical industry faces tremendous financial and competitive pressures to discover and select promising drug candidates more quickly and cost-effectively. Metabolism profiling is a widely used means of identifying toxicity and potential side effects, and selecting the best drug candidates for further study. According to some estimates, 90% of drug metabolites are implicated in adverse drug reactions, and metabolic processes of drugs are always the subject of intense scrutiny in pharmaceutical companies. However, the present-day process of studying metabolites involves animal studies, is labor-intensive and produces results that are chemically inconclusive. For numerous reasons, animal studies are sub-optimal for metabolite profiling. For example, animal studies entail animal sacrifice, often involve liver slice preparations as well as primary cultures of slow reacting hepatocytes and microsomes (e.g., S9 sub-fractions) that vary in potency, and the resulting metabolites are difficult to predict, confirm and quantify. Several alternate methods have also been explored with varying success, including using cultured cell lines (e.g., HepG2 or Huh7), nuclear receptor assays, cell lines stably or transiently expressing appropriate transcription factors and reporter genes, isolated perfused liver cells, plasma membrane vesicles, expressed hepatic proteins (e.g., one or more recombinant cytochrome P450 enzymes, transporters or receptors), and similar biological systems. These have met with limited success and the methods have not ameliorated the problems seen with biological systems.
Clearly, in vitro and ex vivo metabolism profiling are areas where breakthrough technology can be used to overcome current shortcomings.